Novel epoxy pregnanes



United States Patent Q NOVEL EPOXY PREGNANES Percy =L. Julian, Oak Park, and Arthur Magnani, Wilmette, 111., assignors to The Julian Laboratories, Inc., Franklin Park, Ill., a corporation of Illinois No DrawingQ Filed June 26, 1957, Ser. No. 668,025

7 Claims. (01. 260-23955) This invention. relates to new and valuable 11,12

epoxypregnane derivatives. This invention also relates to novel processes for the preparation of these coinpounds; I

The compounds of this invention have central nervdus by-th'e following gener'al'formula:

FORMULA I are represented when R represents hydrogen, hydroxyl or acyloxy; R represents hydrogen or acyl; and E represents an on or 5 bond.

' More specifically, the compounds of this are represented by Formula I when: 7

R represents hydrogen, hydroxyl, acyloxy, preferably alkanoyloxy of 2 to. 6 carbons, w-carboxyalkanoyloxy preferably of 4 to 6 carbons, advantageously hemisuccinyloxy, nontoxic metallic salts, preferably alkali metal salts, and ammonium salts of w-carboxyalkanoyloxy moieties of preferably 4 to .6 carbons or aroyloxy, preferably of 7 to 8 carbons, such as ,benzoyloxy and toluoyloxy.

R represents hydrogen or acyl such as alkanoyl, preferably of from 2'to 6 carbons, aroyl preferably of 7 to .8 carbons, such as benzoyl and toluoyl, w-carboxyalkanoyl invention preferably of from 4 to '6' carbons, advantageously hem i-' succinyl, or nontoxic metallic salts of such hemiester s, preferably alkali metal salts, and ammonium salts. g represent an a or [3 bond.

The compounds of Formula} when R is and R, is: H or acylo'xy are disclosed in. our copending application, Serial No. 647, 465, filed March 21, 1957].

"ice

Advantageous compounds are represented by the general formula:

- FORMULA l1 When R represents hydrogen, hydroxy, hemisuccinyloxy, acetoxy or sodiohemjsuccinyloxy.

.R represents hydrogen, acetate, hemis'uccinyl or sodiuhemisuccinyl.

Preferred compounds are represented by Formula II when R represents hydrogen, hydroxy, hemisuccinyloxy, acetoxy or sodiohemisuccinyloxy; and R represents hydrogen.

' When soluble sedative agents are desired, for instance for intravenous anesthesiology, alkali metal salts of the hemidibasic esters, such as the sodium or potassium salts of either monoor dihemisuccinyl esters, are, preferred.

Such compounds are those in which either one or both of the 3st or 21-hydroxyl groups are esterified.

The 3a-ol compounds of this invention are' advantangeously prepared by another aspect of this invention, namely by selective reduction of the 3-keto analogues. The starting materials for this reduction are 11,12-epoxypregnane-3,20-diones which may or may not be substituted in the 21-position with a hydroxy or acyloxy group.

The preparation of the starting materials are described.

in our copending application Serial Number 647,465, filed March 21, 1957. Selective reduction of the 3-0ne moiety is a generally useful process which can be applied generally to steroids with a S S-H- regnane nucleus which has an 11,12-epoxy substituent. Other permitted variations are N- or A1647 unsaturation as well as lower alkyl substituents at positions 2 or 6. These alternative starting materials are in addition to those which form the compounds of this invention as mentioned above.

The preferred reducing agent is sodium borohydride but other bimetallic hydrides are acceptable, for example potassium borohydride or lithium aluminum hydride. The selectivity of the reaction is largely controlled by the proportion of reducing agent. Preferably, about the stoichiometric amount of reducing agent is used. Excesses of up to three times this quantity of reducing agent or more may be conveniently utilized if the temperature and duration of the reaction are controlled.

The reaction can be run at from about 0 C. to about C. for from several minutes to about six to eight hours. Preferably, the react-ion is-run to completion at ambient temperature, i.e., from about 20 C. to about 40 C. for about one-half to one hour. If an excess of reducing agent is used, the temperature and length of reaction time are limited ,to confine the reduction to the more easily reduced S-keto moiety.

The solvent for the reductionis selected from a wide dride is stable in aqueous solvents, therefore, the reaction.

media for this reagent are aqueous-miscible solventswhich are inert toreduction by the reagents, for example, aqueens-alcoholic mixtures, ethanol, isdpropanol tertalcohol or preferably aqueous methanol. Other reducing agents are sensitive to water, for instance lithium aluminum'hydride, and are used in anhydrous organic media resistant to reduction, such as ethyl ether, tetrahydrofuran or dibutyl ether.

of a reactive group, such as a;21-acyloxy moiety. Inthis case, anhydrous media or inorganic bases'may be employed. Often the 21-hydroxy analogue is desired. In

with a smaller amount of base, for instance in ethylace- 'ta'te or'dimethylformamide with one tofiveequivalents of pyridine or tributylamine. a

The 11a,l2a-epcxypregnane-3a-ol-20-ones of this invention are prepared advantageously by reacting the A pregnene analogue (prepared as describedby Wettstein and Schmidlin, U.S. Patent No. 2,782,211), with a peracid, for instance perbenzoic, or preferably perphthalic acid, in a suitable organic solvent, for instance ether,

benzene or toluene 'to form 1la,12a-epoxypregnane-3,20-

dione. The selective reduction of the 3-one moiety of the 11a,12aep0XideS andthe; other preparative routes described above are fully applicable tothe preparation of these, analogues.

, upon hydrolysis of theacylgroup tojthe active hydroqiy- A group of,monoand, diacylates'haye. been described; for mqdifying the 3,2.1ehy ro y s upe In racticean g acyl substituted compound whichhasactivity as'qsluchio lated compound in vivo can'be used. Illustrative ofsuch this case simultaneous reduction; at 3 and hydrolysis at 21 may be purposely carried out. 1

TIfheZL-atzyloxy compounds areialso. readilypreparcd.

by first preparing 1l,8 ,12fieepoxypregn le-3m-ole2oeone by,

theyabove described method. This compoundis treated with a halogen, acid, preferably'hydrogen'bromide, either aqueous-alcohol, such .as aqueous methanohand' other erg'anic solvents, such as dioxane or chloroform, 'to.

apes; the-1 1, 12-epoxide ring. The 12-,brorno-11-ol is br'orn-inatedat 21 with bromine in an organic solvent, sucha m thylcn hl rid ceti acidor hloroform 9,1

erably. inthe presence of a catalytic amount of, hydrogen bromide. Theresulting;12,2f1-dibromopregnane3d,

v1;1,.-r1iolY-JZQ-orie .is reacted with; an alkali metal salt such as the sodium or potassium: salt of the-desired .acylo7iy moiety whichistobe inserted into position 21 in a water: miscible organic solventinert under the, reaction conditions, such. as acetone or methyl ethyl ketone, prefetablyan additional alkalimetal salt, such as sodium bicar bonate or potassium carbonate, is added to, the, reaction mixture to insure complete reaction, i. e., both inserting.

the. 21-acyloxy group and reforming the 1,1,12-epoxy ring. As an example of this step of;the process, the reace tionais carried out using potassium acetate and sodium bicarbonate in- *acetoneat refluxto give the ZI-acetoxy analogue, 11 3 ,Hfi-epoxy-pregnane-Su,21-diol-20rone 21- acetate. Alternatively, these two reactions may be carried,

outseparately, for instance insertion of the 21-acyloxy 'm'oiety andthen closingthe 11, l2;epoxy ring;

. -The -21;esters may be further esterified at the; 3-posi-.

acylates are oleate', palmitate, ,isobutyrate," stearate, ben

zoate, hemiphthalate, hicotinate, B-naphthoate, glycolate, cyclopentylproprionate, phenylacetate, hemimaleate and preferably acetate, hemisuccinate or sodiohemisllccinate esters.

The following examples will serve .to illustrate' theprep};

aration of the novel compounds a's-well as variations of the processes of thisinvention. The. scope of 'thisinyention is not to be limited by theseexamples since it Wlllfbe obvious to one skilled in the artthat these examples are tion to form diesters with an acyl chloride or anhydride, 7

in an excess; of tertiary organic base, preferably-pyridine,- or in an inert organic liquid with asmaller amount of base; forinstance in ethyl acetate or dimethylformamide with one to five equivalents of; pyridine ortributylamine. This method is particularly useful to prepare mixed diesters. v

. Another means of synthesis of compounds ofthisqinvention; is" mild hydrolysis of the 21-esters prepared as.

above. For instance, the21-acyloxy compound-isreaeted. with dilute methanolic potassiumhydroxide or a catalytic,

amount of sodium methox ide in methanol, solution to form the 21-hydroxy analogue,'which can. be diacylated under-conditions described immediately abovetoform the 3,21-diacylates. e j I ehloride or";anhydridje,-rin anexcess'of tertiary organic basefprefe'rablypyridine, or in an inert organic liquid" 'iconcentratedgto incipient crystallization; Infthis mann mer y illu ative of this in e ion dtha m ficatisns ther farepo' sib fEXampleI I A solution of 50.0 g. of 12fi-epoxypregnane3,20; i

dione in 800 ccrof methanol iscobled'to 15'"C. anda solution consisting of 2.0 g. of sodium borohydride," 1'5 cc. of' 10% aqueouscaustic soda, 100 cc. of pyridine and 100cc. of methanol is added." During the addition 'the temperature of the mixturerisesto 30 C. and 'then grad.

ually drops to about 20C'; Ihe mass-is agitated for;

about 20 minutes. Thereafter'the mass is made strongly acidic by the addition of 4 N hydrobromic acid" (about 400 cc.) and 100 cc. of water. The mixture is agitated,

until crystallization commences. Then water (400 cc.) is l added slowly over a one-half hour period. The slurry is. cooled to 15 C. and then filtered. The filter cake is washed with 250 cc. of 50% aqueous methanol; the

washed cake then is dried; The dried product, 12-bromopregnane-3u,ll-diol-ZO-one; (48.0 g.), melts at 188 to 190C.

chloride is added gradually for 15 minutes, until ;t he.co,lo r. of bromine persists." Themass is then washed withrsuccessive portions of water 'aqueous sodium bicarbonate and water. The washed solution is concentrated to? a volume of about 500 cc., cooled and filtered, The. fi ter cake, after washing with cold methylenechloride and. drying,.weighs 42.2 g. and, melts at to 187 CL- A mixture consisting of. 42.0,-g. of'12,2'1-dibromo added in increments of 1.45 g. at 15 minute intervals, i s. "65

i Mixed-esterscan be obtained alternativelybyselectively; reducing under nonhydrolyniccon'ditions the-3-=keto moiety of-11 B,12fl-epoxypregnane-3,20=dione-21-o1{acylates "which are described in our copendingapplicatiodSebial. l l'o. 647,465 filed March 21, 19 57. The resulting" 1113,12 8- epoxypregnane 3a,2l-diol-ZO-one 21' -acylates3are then op tionallyacylated' atthe 3 hydroxy position'with an an heated, under reflux for five hours. Thereafter the. mass,

ness. The residue is dissolved' absolute ether-and V 1.38' g; (M.P,'. 154 to 157C.) is'isolate 'd,

Treatment'ofthe ZI-abetoxy compound 500 ing.)

50 cc. of dilute tnethanolic potassium hydroxide results upon cooling and evaporation, in the formation of llfl, 12,8-epoxypregnane-3a,21-diol-20-one.

Example II A slurry of 5.0 g. of 11fi,12,3-epoxypregnane-3,20- dione in 80 cc. of methanol is warmed gently to complete solution and thereafter agitated while'cooling to 25 C. A solution of 200 mg. of sodium borohydride in cc. of pyridine, 10 cc. of methanol and 1.5 cc. of 10% aqueous caustic soda is added to the slurry. After the addition, the solid dissolves completely and the temperature rises to 34 C. The mass is agitated for minutes, during which time the temperature falls to 30 C. To this mass is added 500 cc. of water in five equal portions and the resultant slurry is agitated for one hour. The mixture is filtered and the filter cake is washed with water. After drying, 4.21 g. of product, 115,12p-epoxypregnane-3a-ol-20-one, (M.P. l30-140 C.) is recovered.

The crude product is dissolved in 30 cc. of methanol and the solution concentrated to a volume of 15 cc. Upon the addition of 5 cc. of 4 N hydrobromic acid, and cooling, the bromohydrin crystallizes. This product, on titrating with methanolic caustic soda to a permanent end point with phenolphthalein and then watering out of solution, gives 1lfl,12p-epoxypregnane-3a-ol-20-one, M.P. 144-146 C.

A mixture of 850 mg. of the crude epoxypregnanolone, 1.5 cc. of pyridine and 1 cc. of acetic anhydride is heated on a steam bath for one-half hour and then agitated for one-half hour. The mass is diluted with water and extracted with ether. The ether extract is washed with water, aqueous caustic soda and finally with water. The washed solution is concentrated to a low volume. The product crystallizes from ether-petroleum ether. The

crystal slurry is filtered and the cake washed with 50/50 ether-petroleum ether, resulting in 115,12B-epoxypregnane-3a-ol-20-one acetate, M.P. 158-160 C.

Treatment of this product, after dissolving in acetone, with 4 N hydrobromic acid yields the corresponding bromohydrin, M.P. 196-198 C.

Example III A suspension of 2.5 g. of 11a,12a-epoxypregnane-3,20- dione, prepared by reacting A -pregnene-3,20-dione with monoperthalic acid in ether, in 50 cc. of ethanol is reacted with 100 mg. of sodium borohydride as in Example 11 to give 11u,12a-epoxypregnane-3a-ol-20-one. The

crude epoxide (1.8 g.) is reacted with isocaproyl chloride.

(2.5 cc.) in 25 ml. of ethyl acetate and 1 ml. of pyridine at room temperature for several hours. The reaction mixture is evaporated at the water pump, washed with water and extracted into ether. The ether extracts are washed with water, dilute carbonate and dried. After reducing the volume, petroleum ether is added. Cooling separates crystals of 11a,12a-epoxypregnane-3a-ol-20-one isocaproate.

Example IV A solution of 1.0 g. of 11B,12 8-epoxypregnane-3a,21- diol--one in 50 cc. of acetone with 1 cc. of pyridine and 1.0 g. of succinic anhydride is stirred for eight hours. The reaction mixture is quenched in ice water and filtered. The resulting solid is l1,8,IZB-epoxypregnane-Sa-Zl-diol- 20-one dihemisuccinate.

A small amount (500 mg.) of the diester in purified dioxane ml.) is treated with an excess of sodium metal to separate the disodium salt. The potassium salt is prepared in like manner using an excess of potassium metal.

Example V A solution of 6.2 g. of 11,8,l2fi-epoxypregnane-3,20- dione-Zl-ol propionate in 100 cc. of methanol is reacted Example VI A solution of 2.0 g. of 1lfl,l2p-epoxypregnane3a,2ldiol-20-one in 25 ml. of dry pyridine is reacted F with 2 cc. of acetic anhydride as described in Example II to give 11,3,12fl-epoxypregnane-3a,21 diol-20-one diacetate. I

Example VII.

A suspension of 4.8 g. of 1118,125-ep0xypregnane-2lol-3,20-dione hemisuccinate in cc. of methanol and 25 cc. of water is reacted with 100 mg. of sodium borohydride in the presence of 25 ml. of tributylamine. The reaction mixture, after one hour, is evaporated in vacuo. The residue is diluted with water, carefully neutralized with dilute acetic acid and extracted with ether andethyl acetate. The organic extracts are washed with water. Concentration and trituration with isooctane gives 11p, IZB-epoxypregnane-S a,21-diol-20-one 21 hemisuccinate. A solution of this ester (0.1 g.) in 500 ml. of ether is reacted with potassium metal to give the potassium salt. A solution of this ester (0.1 g.) in 500 ml. of ether is reacted with sodium metal to give the sodium salt.

Example VIII A mixture of 10.5 g. of 12,21-dibromopregnane-3u,11- diol-ZO-one prepared as in Example I, in 200 ml. of acetone is reacted as in Example I, using sodium benzoate rather than potassium acetate. The product obtained as above is 11B,12,8-epoxypregnane-3a,21-diol-20-one 21- benzoate.

A mixture of 1.0 g. of the benzoate, 2.0 cc. of pyridine and 1 ml. 'of butyric anhydride is allowed to stand at room temperature for two hours. The reaction mixture is quenched with water and extracted with ether. The washed and dried ether extracts are concentrated to give crystals of the desired 3-butyrate 21-benzoate ester.

Example IX A solution of 500 mg. of 1l/3,12/3-epoxypregnane-3a, 21-diol-20-one, prepared as in Example I, in 50 cc. of acetone with 0.5 ml. of pyridine is stirred overnight with 0.6 g. of glutaric anhydride. After quenching the reaction mixture in an ice slurry, the solid is separated by filtration to give 1118,12/8-epoxypregnane-3u,21-dio1-20- one dihemiglutarate.

A small amount of this solid is dissolved in ether and reacted with a kernel of sodium to give the solid disodium salt.

Example X A mixture of 5.2 g. of 12,21-dibromopregnane-3a,11- diol-20-one, prepared as in Example I, in 100 ml. of acetone is reacted and worked up as in Example I, but using 11.5 g. of potassium caproate rather than potassium acetate. The product obtained from the reaction mixture is 11,6,l2fi-epoxypregnane-3a,21-diol-20-one 2l-caproate.

A solution of 500 mg. of this ester is dissolved in ether with a few drops of pyridine. About 300 mg. of succinic anhydride in ether is added at reflux. The ether is removed and the residue quenched in water to yield the solid' 3-hemisuccinate 2.1-caproate salt.

V 7 Whatis claimed is: LA chemicalv compound having the following forin which R is a membef selected from the group consisting of hydrogen, hydroxyl, alkanoyloxy having 2 to V '6 Zcarbc'm;atom,; w qarboxya lkanoyloxy having 4; to 6 icarbon-yatoms; alkali ni'etalsalts of w-carhoxyalkanqyloxy" moieties 'havingt t to 6l vcarbon atoms; and benzoyloxy;

'R is a member selected from the group consisting of hydrogen; alkanoyl having 210 6 carb0n atoms, benzoyl,

w-carboxyialkanoyl having 4 to 6 carbon atoms, alkali metal salts of w-vcarboxyalk anoyl moieties hay/ ing. 4 to 6' carbon atoms. is t .L x

2. 11B,12B-ep0xypregnaue-3a,2l-diol-ZO-onel 3. 115,12fl-epoxypregnane-3a-ol-20-one.

' "4. .1118, 12B-epoxy-2Lhemisuccinyloxypregnane+=3a-=o1- l 5. 11B,12/3 epoxy-21 sodiohemisuccinyloxipregnane 3oc-vO l*ZO-0ne. u z 10 -6. 2lracetoxy-l1B,12B-epoxypregnanefia-pl-ZO-one.

OTHER REFERENCES 0 Chemistiy and Industry, 1954, by Woodset al ipjages' 

1. A CHEMICAL COMPOUND HAVING THE FOLLOWING FORMULA: 